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Epigenome-wide change and variation in DNA methylation in childhood: trajectories from birth to late adolescence.

ABSTRACT: DNA methylation (DNAm) is known to play a pivotal role in childhood health and development, but a comprehensive characterization of genome-wide DNAm trajectories across this age period is currently lacking. We have therefore performed a series of epigenome-wide association studies in 5019 blood samples collected at multiple time-points from birth to late adolescence from 2348 participants of two large independent cohorts. DNAm profiles of autosomal CpG sites (CpGs) were generated using the Illumina Infinium HumanMethylation450 BeadChip. Change over time was widespread, observed at over one-half (53%) of CpGs. In most cases, DNAm was decreasing (36% of CpGs). Inter-individual variation in linear trajectories was similarly widespread (27% of CpGs). Evidence for non-linear change and inter-individual variation in non-linear trajectories was somewhat less common (11 and 8% of CpGs, respectively). Very little inter-individual variation in change was explained by sex differences (0.4% of CpGs) even though sex-specific DNAm was observed at 5% of CpGs. DNAm trajectories were distributed non-randomly across the genome. For example, CpGs with decreasing DNAm were enriched in gene bodies and enhancers and were annotated to genes enriched in immune-developmental functions. In contrast, CpGs with increasing DNAm were enriched in promoter regions and annotated to genes enriched in neurodevelopmental functions. These findings depict a methylome undergoing widespread and often non-linear change throughout childhood. They support a developmental role for DNA methylation that extends beyond birth into late adolescence and has implications for understanding life-long health and disease. DNAm trajectories can be visualized at http://epidelta.mrcieu.ac.uk.

SUBMITTER: Mulder RH

PROVIDER: S-EPMC8033147 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Epigenome-wide change and variation in DNA methylation in childhood: trajectories from birth to late adolescence.

Mulder Rosa H RH Neumann Alexander A Cecil Charlotte A M CAM Walton Esther E Houtepen Lotte C LC Simpkin Andrew J AJ Rijlaarsdam Jolien J Heijmans Bastiaan T BT Gaunt Tom R TR Felix Janine F JF Jaddoe Vincent W V VWV Bakermans-Kranenburg Marian J MJ Tiemeier Henning H Relton Caroline L CL van IJzendoorn Marinus H MH Suderman Matthew M

Human molecular genetics 20210301 1

DNA methylation (DNAm) is known to play a pivotal role in childhood health and development, but a comprehensive characterization of genome-wide DNAm trajectories across this age period is currently lacking. We have therefore performed a series of epigenome-wide association studies in 5019 blood samples collected at multiple time-points from birth to late adolescence from 2348 participants of two large independent cohorts. DNAm profiles of autosomal CpG sites (CpGs) were generated using the Illum ...[more]

PMID: 33450751

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Project description:BackgroundDNA methylation has been shown to be associated with adiposity in adulthood. However, whether similar DNA methylation patterns are associated with childhood and adolescent body mass index (BMI) is largely unknown. More insight into this relationship at younger ages may have implications for future prevention of obesity and its related traits.MethodsWe examined whether DNA methylation in cord blood and whole blood in childhood and adolescence was associated with BMI in the age range from 2 to 18 years using both cross-sectional and longitudinal models. We performed meta-analyses of epigenome-wide association studies including up to 4133 children from 23 studies. We examined the overlap of findings reported in previous studies in children and adults with those in our analyses and calculated enrichment.ResultsDNA methylation at three CpGs (cg05937453, cg25212453, and cg10040131), each in a different age range, was associated with BMI at Bonferroni significance, P < 1.06 × 10-7, with a 0.96 standard deviation score (SDS) (standard error (SE) 0.17), 0.32 SDS (SE 0.06), and 0.32 BMI SDS (SE 0.06) higher BMI per 10% increase in methylation, respectively. DNA methylation at nine additional CpGs in the cross-sectional childhood model was associated with BMI at false discovery rate significance. The strength of the associations of DNA methylation at the 187 CpGs previously identified to be associated with adult BMI, increased with advancing age across childhood and adolescence in our analyses. In addition, correlation coefficients between effect estimates for those CpGs in adults and in children and adolescents also increased. Among the top findings for each age range, we observed increasing enrichment for the CpGs that were previously identified in adults (birth Penrichment = 1; childhood Penrichment = 2.00 × 10-4; adolescence Penrichment = 2.10 × 10-7).ConclusionsThere were only minimal associations of DNA methylation with childhood and adolescent BMI. With the advancing age of the participants across childhood and adolescence, we observed increasing overlap with altered DNA methylation loci reported in association with adult BMI. These findings may be compatible with the hypothesis that DNA methylation differences are mostly a consequence rather than a cause of obesity.

Project description:ImportanceThe understanding of the development of psychopathology has been hampered by a reliance on cross-sectional data and symptom- or disorder-centered methods. Person-centered methods can accommodate both the problems of comorbidity and the movement between different psychopathological states at different phases of development.ObjectiveTo examine the profiles and map the trajectories of psychopathology from early childhood to late adolescence.Design, setting, and participantsThis cohort study used 2 longitudinal nationally representative community-based cohorts from the Growing Up in Ireland study covering developmental periods from early childhood to late adolescence. Data in this investigation came from children and their families who participated in all waves of cohorts recruited in 2008 (children ages 3, 5, and 9 years) and 1998 (adolescents ages 9, 13, and 17 or 18 years). Both samples were weighted to account for representation and attrition. Latent transition analyses were used to map the trajectories of psychopathology. Data were analyzed between October 2020 and September 2021.Main outcomes and measuresPsychopathology was measured using the Strengths and Difficulties Questionnaire at all ages in both samples.ResultsA total of 13 546 individuals were included in the analyses. In the child cohort, mean (SD) age was 3.0 [0.01] years; 3852 (51.3%) were male participants. In the adolescent cohort, mean age was 9.0 (0.1) years; 3082 (51.0%) were male participants. Four profiles were identified in both cohorts that could be broadly labeled as no psychopathology (incidence range, 60%-70%), high psychopathology (incidence range, 3%-5%), externalizing problems (incidence range, 15%-25%), and internalizing problems (incidence range, 7%-12%). Transition between the profiles was common in both cohorts, with 3649 of 7507 participants (48.6%) in the child cohort and 2661 of 6039 participants (44.1%) in the adolescent cohort moving into 1 of the 3 psychopathology profiles at some point in development. Transition to the high psychopathology profile was most often preceded by externalizing problems. Approximately 3% to 4% of the sample had persistent psychopathology (child cohort, 203 participants [2.7%]; adolescent cohort, 216 participants [3.6%]). All psychopathology profiles were more common in boys in early life but, by late adolescence, girls were more likely to have internalizing problems. In a cross-cohort comparison at age 9, there were differences in the sex distributions of the profiles between the samples.Conclusions and relevanceUsing person-centered methods, this study demonstrated that from early life young peoples' experience of psychopathology is dynamic-they can move between different mental health problems; for most children, these problems are transient, but a small proportion (fewer than 5%) have persistent difficulties. In the context of finite resources, optimizing care requires the early identification of those with persistent phenomena.

Project description:BackgroundAsthma heritability has only been partially explained by genetic variants and is known to be sensitive to environmental factors, implicating epigenetic modifications such as DNA methylation in its pathogenesis.MethodsUsing data collected in the Avon Longitudinal Study of Parents and Children (ALSPAC), we assessed associations of asthma and wheeze with DNA methylation at 7.5 and 16.5 years, at over 450,000 CpG sites in DNA from the peripheral blood of approx. 1000 participants. We used Mendelian randomization (MR), a method of causal inference that uses genetic variants as instrumental variables, to infer the direction of association between DNA methylation and asthma.ResultsWe identified 302 CpGs associated with current asthma status (FDR-adjusted P value < 0.05) and 445 with current wheeze status at 7.5 years, with substantial overlap between the two. Genes annotated to the 302 associated CpGs were enriched for pathways related to movement of cellular/subcellular components, locomotion, interleukin-4 production and eosinophil migration. All associations attenuated when adjusted for eosinophil and neutrophil cell count estimates. At 16.5 years, two sites were associated with current asthma after adjustment for cell counts. The CpGs mapped to the AP2A2 and IL5RA genes, with a - 2.32 [95% CI - 1.47, - 3.18] and - 2.49 [95% CI - 1.56, - 3.43] difference in percentage methylation in asthma cases respectively. Two-sample bi-directional MR indicated a causal effect of asthma on DNA methylation at several CpG sites at 7.5 years. However, associations did not persist after adjustment for multiple testing. There was no evidence of a causal effect of asthma on DNA methylation at either of the two CpG sites at 16.5 years.ConclusionThe majority of observed associations are driven by higher eosinophil cell counts in asthma cases, acting as an intermediate phenotype, with important implications for future studies of DNA methylation in atopic diseases.

Project description:BackgroundMaternal pre-pregnancy obesity is an established risk factor for childhood obesity. Investigating epigenetic alterations induced by maternal obesity during fetal development could gain mechanistic insight into the developmental origins of childhood obesity. While obesity disproportionately affects underrepresented racial and ethnic mothers and children in the USA, few studies investigated the role of prenatal epigenetic programming in intergenerational obesity of these high-risk populations.MethodsThis study included 903 mother-child pairs from the Boston Birth Cohort, a predominantly urban, low-income minority birth cohort. Mother-infant dyads were enrolled at birth and the children were followed prospectively to age 18 years. Infinium Methylation EPIC BeadChip was used to measure epigenome-wide methylation level of cord blood. We performed an epigenome-wide association study of maternal pre-pregnancy body mass index (BMI) and cord blood DNA methylation (DNAm). To quantify the degree to which cord blood DNAm mediates the maternal BMI-childhood obesity, we further investigated whether maternal BMI-associated DNAm sites impact birthweight or childhood overweight or obesity (OWO) from age 1 to age 18 and performed corresponding mediation analyses.ResultsThe study sample contained 52.8% maternal pre-pregnancy OWO and 63.2% offspring OWO at age 1-18 years. Maternal BMI was associated with cord blood DNAm at 8 CpG sites (genome-wide false discovery rate [FDR] < 0.05). After accounting for the possible interplay of maternal BMI and smoking, 481 CpG sites were discovered for association with maternal BMI. Among them 123 CpGs were associated with childhood OWO, ranging from 42% decrease to 87% increase in OWO risk for each SD increase in DNAm. A total of 14 identified CpG sites showed a significant mediation effect on the maternal BMI-child OWO association (FDR < 0.05), with mediating proportion ranging from 3.99% to 25.21%. Several of these 14 CpGs were mapped to genes in association with energy balance and metabolism (AKAP7) and adulthood metabolic syndrome (CAMK2B).ConclusionsThis prospective birth cohort study in a high-risk yet understudied US population found that maternal pre-pregnancy OWO significantly altered DNAm in newborn cord blood and provided suggestive evidence of epigenetic involvement in the intergenerational risk of obesity.

Dataset Information

Epigenome-wide change and variation in DNA methylation in childhood: trajectories from birth to late adolescence.

Publications

Epigenome-wide change and variation in DNA methylation in childhood: trajectories from birth to late adolescence.

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